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This Article Accepted manuscript (PDF) Supplementary data All Versions of this Article: JOE-08-0376v1 200/1/107    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Segawa, K. Articles by Shimomura, I. Search for Related Content PubMed PubMed Citation Articles by Segawa, K. Articles by Shimomura, I.

K Segawa, Departments of Metabolic Medicine, Graduate School of Medicine, Osaka University, Suita-shi, Japan
M Matsuda, Institute of Clinical Research, National Hospital Organization Kure Medical Center, Kure, 737-0023, Japan
A Fukuhara, Departments of Metabolic Medicine, Graduate School of Medicine, Osaka University, Suita-shi, Japan
K Morita, Departments of Metabolic Medicine, Graduate School of Medicine, Osaka University, Suita-shi, Japan
Y Okuno, Departments of Metabolic Medicine, Graduate School of Medicine, Osaka University, Suita-shi, Japan
R Komuro, Departments of Metabolic Medicine, Graduate School of Medicine, Osaka University, Suita-shi, Japan
I Shimomura, Departments of Metabolic Medicine, Graduate School of Medicine, Osaka University, Suita-shi, Japan

Correspondence: Morihiro Matsuda, Email: morihiro-m{at}kure-nh.go.jp

Abstract

Adiponectin is exclusively expressed in adipose tissue and secreted from adipocytes, and shows anti-diabetic and anti-atherogenic properties. However, the precise transcriptional mechanism of adipocyte-specific gene expression of adiponectin remains elusive. In this study, the 5’ flanking promoter region of human adiponectin gene was analyzed using UCSC genome browser, and a 10390-bp fragment, containing an evolutionally conserved region among species, was investigated. The luciferase reporter assay using this fragment identified a novel distal enhancer of human adiponectin gene. Promoter constructs with the distal enhancer exhibited high promoter activities in 3T3-L1 mature adipocytes. However, no such activity was observed in other types of cell lines. The distal enhancer is highly conserved, and contains two completely conserved CCAAT boxes. In 3T3-L1 mature adipocytes, deletion or each point mutation of these CCAAT boxes markedly reduced luciferase activity driven by adiponectin promoter. Knockdown of CCAAT-enhancer binding protein (C/EBP) using small interfering RNA diminished adiponectin mRNA expression and luciferase activity driven by adiponectin promoter with the distal enhancer. However, adiponectin promoter with each mutation of two CCAAT boxes in the distal enhancer did not respond to knockdown of C/EBP expression. Furthermore, C/EBP bound to the distal enhancer both in vitro and in vivo. We also identified a proximal promoter region responsible for transcriptional activation by the distal enhancer in human adiponectin gene. Our results indicate that C/EBP plays a pivotal role in the transcription of human adiponectin gene via the distal enhancer and proximal region in its promoter.

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